Project Summary For women, the menopausal transition (MT) is a critical period of decline in bone strength, during which about half the lifetime loss in bone mineral density (BMD) occurs. While clinically, and in research, BMD is the primary indicator for osteoporosis, it does not reveal the changes in bone structure needed to fully understand age-related loss in strength. This proposal seeks to better elucidate the structural changes that underlie loss in strength during the MT by examining relative changes in endocortical expansion (bone loss) versus periosteal expansion (bone gain). These two features define bone strength, but the manner in which each of these structural indices changes during the MT is largely unexplored. Our central hypothesis is that bone strength declines earlier and more rapidly in women with wide bones compared to women with narrow bones. This hypothesis is guided by promising preliminary data findings in our epidemiologic and cadaver studies which suggest that individualized trajectories of strength-decline may be established during the initial phase of bone loss for women, and that external bone size (e.g., bone width, total cross-sectional area) may identify women in a high fracture-risk group. We will first validate new bone strength indices and test for the biological basis of our hypothesis in cadaveric tissue (Aim 1). Our work in cadaveric tissue has shown greater intra-cortical porosity in wide compared to narrow bones, suggesting different strength-decline trajectories may arise from BMU-based remodeling. Because this can only be studied precisely using histological sections, we will combine cadaveric studies (Aim 1) with living human studies (Aims 2,3) to provide a biological basis for observations derived from longitudinal data. We will test our central hypothesis using two existing longitudinal databases with image-data acquired over 20 years among 40-60 year-old women as they transition from pre- to post-menopause. We will relate baseline bone traits to structural and strength changes during the MT in a weight-bearing, fracture prone bone (proximal femur) and a nonweight-bearing, non-fracture prone bone (metacarpal) to assess its clinical value for diagnosing strength changes at the hip. Specifically, we propose to 1) test for associations between baseline external bone size and changes in strength indices during the MT for white women in the Michigan Bone Health and Metabolism Study (MBHMS) and then 2) test whether the factors that differentiate between white women who lose more vs. less bone strength during the MT in the MBHMS are predictive of MT-related strength declines in white and black women followed across the MT over 20 years in the Study of Women?s Health Across the Nation (SWAN). This study addresses a significant gap in scientific knowledge that impedes our ability to optimize fracture prevention strategies. If our hypotheses prove correct, baseline external bone size may be used as an additional parameter to identify women most likely to lose bone strength rapidly during the MT and who might benefit from early intervention. Successful completion of our Aims will provide fundamental new information about what specific structural and material parameters can best inform clinical decisions.